3-alkoxyisothiazoles

ABSTRACT

Disclosed are certain novel 3-alkoxyisothiazoles. The 3-alkoxyisothiazoles and compositions containing them exhibit useful biocidal properties.

This invention relates to novel 3-alkoxyisothiazoles (hereinafterreferred to at times as "isothiazoles" or "alkoxyisothiazoles"), tobiocidal compositions containing them, and to their utilization in thecontrol of living organisms.

These novel 3-alkoxyisothiazoles can be represented by the formula##EQU1## wherein Y is an alkyl group of 1 to 18 carbon atoms; acycloalkyl group of 3 to 8 carbon atoms; an aralkyl group of up to 8carbon atoms; a halogen-, lower alkyl-, or lower alkoxy-substitutedaralkyl group of up to 10 carbon atoms; a carbalkoxyalkyl group of up to12 carbon atoms; a dialkylaminoalkyl group of up to 12 carbon atoms; ahaloalkyl group of up to 12 carbon atoms; an alkoxyalkyl group of up to12 carbon atoms; an alkylthioalkyl group of up to 12 carbon atoms; analkenyl group of up to 12 carbon atoms; or an alkynyl group of up to 12carbon atoms;

Z is hydrogen, halogen, a nitro group, a cyano group, a carboxy group, acarbalkoxy group of up to 8 carbon atoms, a carbamoyl group, an aminogroup, an aralkyl group of up to 8 carbon atoms, or a lower alkyl group;and

Z' is hydrogen, halogen, an alkyl group of up to 8 carbon atoms, anaralkyl group of up to 8 carbon atoms, a lower alkylsulfinyl group, anaralkylsulfinyl group of up to 8 carbon atoms, a lower alkylsulfonylgroup, an aralkylsulfonyl group of up to 8 carbon atoms, or analkylamino group of up to 8 carbon atoms.

These 3-alkoxyisothiazoles can form novel salts with strong organic orinorganic acids. The salts also exhibit biocidal activity.

Where the expression "lower" is employed in conjunction with terms, suchas for example, alkyl, alkylsulfinyl, alkylsulfonyl or haloalkyl, it isintended to indicate that the alkyl portion of the substituent group hasa carbon content of 1 to 4 carbon atoms. Typically, the alkyl or alkylportion may be methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and thelike.

Representative Y substituents include methyl, ethyl, propyl, isopropyl,butyl, hexyl, octyl, dodecyl, octadecyl, cyclohexyl, benzyl,4-chlorobenzyl, trichlorobenzyl, carbethoxymethyl, carbethoxyethyl,diethylaminoethyl, diethylaminomethyl, chloroethyl, chloromethyl,bromomethyl, allyl, propargyl, methoxymethyl, 2-ethoxyethyl,methylthiomethyl, and 4-octynyl.

Representative Z substituents include hydrogen, methyl, ethyl, propyl,isopropyl, butyl, benzyl, chloro, bromo, iodo, cyano, carboxy,carbethoxy, carbamoyl, amino, and nitro.

Representative Z' substituents include hydrogen, methyl, ethyl, propyl,isopropyl, butyl, octyl, benzyl, chloro, bromo, methylsulfinyl,ethylsulfinyl, butylsulfinyl, benzylsulfinyl, methylsulfonyl,ethylsulfonyl, propylsulfonyl, benzylsulfonyl, ethylamino, andn-butylamino.

Typical compounds which fall within the scope of this invention include,for example,

3-methoxyisothiazole,

3-ethoxyisothiazole,

3-isopropoxyisothiazole,

3-n-hexyloxyisothiazole,

4-bromo-3-methoxyisothiazole,

4-iodo-3-methoxyisothiazole,

4-nitro-3-methoxyisothiazole,

4-cyano-3-methoxyisothiazole,

4-carbamoyl-3-methoxyisothiazole,

4-carboxy-3-methoxyisothiazole,

4-bromo-3-n-hexyloxyisothiazole,

3-n-dodecyloxyisothiazole,

3-benzyloxyisothiazolone,

3-trichlorobenzyloxyisothiazole,

3-carbethoxymethoxyisothiazole,

3-[2-(N,N-diethylamino)ethoxy]isothiazole,

3-(2-chloroethoxy)isothiazole,

3-allyloxyisothiazole,

3-(2-propynyloxy)isothiazole,

3-methoxymethoxyisothiazole,

5-chloro-3-methoxymethoxyisothiazole,

4-cyano-3-n-dodecyloxyisothiazole,

4-cyano-3-n-hexyloxyisothiazole,

3-n-propoxyisothiazole,

4-carboxy-3-n-dodecyloxyisothiazole,

3-n-butoxyisothiazole,

4-carboxy-3-n-butoxyisothiazole,

4-carboxy-3-n-hexyloxyisothiazole,

4-bromo-3-n-propoxyisothiazole,

4-cyano-3-n-propoxyisothiazole,

4-carbamoyl-3-n-propoxyisothiazole,

4-amino-3-n-propoxyisothiazole

4-chloro-3-methoxyisothiazole,

5-benzyl-3-methoxyisothiazole,

5-bromo-3-methoxyisothiazole,

5-chloro-3-methoxyisothiazole,

4,5-dichloro-3-methoxyisothiazole,

4,5-dibromo-3-methoxyisothiazole,

4-chloro-5-bromo-3-methoxyisothiazole,

4-bromo-5-chloro-3-methoxyisothiazole,

4-chloro-5-benzyl-3-methoxyisothiazole,

4-bromo-5-benzyl-3-methoxyisothiazole,

4-methyl-3-methoxyisothiazole,

4-ethyl-3-methoxyisothiazole,

4-butyl-3-methoxyisothiazole,

4-methyl-5-ethyl-3-methoxyisothiazole,

4,5-dimethyl-3-methoxyisothiazole,

4-methyl-5-chloro-3-methoxyisothiazole,

4-propyl-5-chloro-3-methoxyisothiazole,

4-butyl-5-chloro-3-methoxyisothiazole,

4-methyl-5-bromo-3-methoxyisothiazole,

4-ethyl-5-bromo-3-methoxyisothiazole,

4-ethyl-5-benzyl-3-methoxyisothiazole,

4-propyl-5-benzyl-3-methoxyisothiazole,

4-cyano-5-methylsulfinyl-3-methoxyisothiazole,

4-cyano-5-ethylsulfinyl-3-methoxyisothiazole,

4-cyano-5-benzylsulfinyl-3-methoxyisothiazole,

4-cyano-5-methylsulfonyl-3-methoxyisothiazole,

4-cyano-5-butylsulfonyl-3-methoxyisothiazole,

4-cyano-5-benzylsulfonyl-3-methoxyisothiazole,

4-carboxy-5-methylthio-3-methoxyisothiazole,

4-carbamoyl-5-methylthio-3-methoxyisothiazole,

4-cyano-5-n-butylamino-3-methoxyisothiazole,

4-cyano-5-ethylamino-3-methoxyisothiazole,

4-carbethoxy-3-methoxyisothiazole,

4-nitro-5-chloro-3-methoxyisothiazole, and

4-cyano-5-methyl-3-methoxyisothiazole.

The 3-alkoxyisothiazoles of the invention can be prepared by reactingwith a halogenating agent a disulfide-imidate hydrochloride having theformula ##EQU2## wherein R and R' are hydrogen, saturated alkyl groups,or araalkyl groups and Y is as defined above. Typical halogenatingagents include chlorine, bromine, sulfuryl chloride, sulfuryl bromide,N-chlorosuccinimide, N-bromosuccinimide, iodine monochloride and thelike. Chlorine and sulfuryl chloride are the preferred halogenatingagents.

Temperature is not critical to the cyclization reaction process, and anydesired temperature may be utilized. Generally and preferably thecyclization will be carried out in the range of about 0° to 60° C.

The reaction is generally carried out in an inert non-aqueous solvent,such as benzene, toluene, xylene, ethyl acetate, ethylene dichloride,2-nitropropane, and the like.

The isothiazoles may be obtained as their isothiazolium salts during thecyclization process. Such salts have the following structure: ##EQU3##wherein Y, R, and R' are as defined above, and A is halogen. Wheredesired or necessitated, an acid acceptor can be incorporated in thereaction medium to avoid isothiazolium salt formation. Typical acceptorswhich can be utilized include t-amine bases, such as, for example,pyridine and triethylamine. It should be noted at this point that theisothiazolium salts can also be transformed or neutralized to freeisothiazoles by being contacted with water or bases. Such proceduresare, of course, well known to those skilled in the art.

To separate, if desired, the products prepared by the novel process ofthe invention from the reaction solution, any of the known techniquesmay be employed. Generally, separation will involve one or more of thesteps of distillation, crystallization, filtration and the like.

For the cyclization of each mole of the disulfideimidate, 3 moleequivalents of the halogenating agent are required. When more than 3mole equivalents of the halogenating agent are provided, thehalogenation can occur at the 5-position and at both the 4- and 5-positions. Thus, when 5 mole equivalents of the halogenating agent arepresent, a 5-monohalogenated alkoxyisothiazole can be prepared, and when7 mole equivalents of the halogenating agent are present, a4,5-dihalogenated alkoxyisothiazole can be obtained.

The 4-halo and 4,5-dihalo-3-alkoxyisothiazoles can also be prepared byhalogenation of a 3-alkoxyisothiazole. Preparation of alkoxyisothiazoleshaving the 4- and 5- positions substituted with different halogen atomsis achieved by the halogenation of an isothiazolone already halogenatedat one of the two positions in question. For example, a4-bromo-5-chloro-3-alkoxyisothiazole can be obtained by bromination of a5-chloro-3-alkoxyisothiazole. The starting isothiazole can, of course,be prepared by the cyclization of a disulfide-imidate as describedherein.

The disulfide-imidates which are cyclized to form the3-alkoxyisothiazoles are generally prepared fromβ,β'-dithiodipropionitriles which are in turn prepared from the reactionof acrylonitriles with ammonium tetrasulfide. The reaction of olefinswith ammonium tetrasulfide to form disulfides is a reaction well knownin the art. A β,β'-dithiodipropionitrile prepared from acrylonitriles inthe manner stated above is then reacted with a suitable alcohol in thepresence of hydrogen chloride to give the disulfide-imidatehydrochloride. The reaction is generally carried out in the presence ofan inert non-aqueous solvent. The reaction can be run over a widetemperature range, with -20° C. to +100° C. being the preferred range.

Salts of the novel 3-alkoxyisothiazoles of the invention are alsobiocidally active. Preparation of the salts of these3-alkoxyisothiazoles is readily achieved by reacting a3-alkoxyisothiazole with a strong acid. The salts can be represented byFormula III, above, wherein A represents an anion of the strong acid.Typical strong acids include hydrobromic, nitric, sulfuric, perchloric,chlorosulfuric, chloroacetic, maleic, p-toluenesulfonic, hydrochloric,and the like. Separation of these salts from the reaction medium can beaccomplished by any convenient means.

The 4-cyano, 4-carboxy, 4-carbalkoxy, 4-carbamoyl, 4-nitro, and4-amino-3-alkoxyisothiazoles are all prepared by various classicalreactions from the appropriate 3-alkoxyisothiazoles. A4-bromo-3-alkoxyisothiazole, prepared as described above, is reactedwith an equimolar or excess amount of cuprous cyanide, in a polar,non-hydroxylic solvent such as dimethylformamide, to give the4-cyano-3-alkoxyisothiazole. The 4-carbamoyl-3-alkoxyisothiazoles areprepared by the hydrolysis of 4-cyano-3-alkoxyisothiazoles with sulfuricacid. When the carbamoyl derivative is hydrolyzed with nitrous acid, a4-carboxy-3-alkoxyisothiazole is obtained. In the hydrolysis reactions,an equimolar amount or an excess of sulfuric acid or nitrous acid isused, and the reactions can be carried out in a wide variety ofsolvents. The 5-halo and 5-alkyl-4-carboxy and4-carbamoyl-3-alkoxyisothiazoles are prepared from the corresponding4-cyano-3-alkoxyisothiazole, which is in turn prepared from3-alkoxyisothiazole.

The 4-nitro-3-alkoxyisothiazoles are prepared by a classical nitrationof 3-alkoxyisothiazole in a nitric acid-sulfuric acid mixture, generallyusing an equimolar amount of nitric acid and excess sulfuric acid. The4-amino-3-alkoxyisothiazoles can be prepared by reacting a4-carbamoyl-3-alkoxyisothiazole with aqueous sodium hypobromite orsodium hypochlorite, the well-known Hofmann rearrangement.

The 3-alkoxyisothiazoles of this invention can also be prepared byalkylation of a 3-hydroxyisothiazole. This reaction can be representedas follows: ##EQU4## wherein Y, Z, and Z' are as defined above and X isa halogen, such as bromine, chlorine, or iodine. This reaction may alsoyield 3-isothiazolones having the formula ##EQU5## wherein Y, Z, and Z'are as defined above, as well as the 3-alkoxyisothiazoles. Generally, anacid acceptor is used to facilitate the alkylation reaction. Among thesuitable acid acceptors which can be used are inorganic bases, such asalkali and alkaline earth metal hydroxides, alcoholates, hydrides,amides, and carbonates, and organic bases, such as trialkylamines andpyridine. The ratio of the reactants -- 3-hydroxyisothiazole,alkylhalide, and acid acceptor -- will usually be equimolar. However, anexcess of any of the reactants can be used.

The alkylation reaction can be carried out in almost any solvent whichwill not interfere with the reaction, including water, alcohols,aliphatic and aromatic hydrocarbons, ethers, esters, amides, nitriles,and the like. The alkylhalide reagent itself can also be used as asolvent for the reaction. The alkylation reaction will proceed over abroad temperature range and temperature is not critical to the reaction.Generally, the alkylation will be carried out in the range of about 0°to 100° C.

The 3-hydroxyisothiazoles which are used as starting materials in thealkylation reaction can be prepared by several methods.3-Hydroxyisothiazoles having the formula ##EQU6## wherein M and M' arehydrogen, halogen, or saturated alkyl groups can be prepared by thecyclization of a disulfide-amide having the formula ##EQU7## wherein M"and M'" are hydrogen or saturated alkyl groups. The cyclization isaccomplished by reacting the disulfide-amide with a halogenating agentunder conditions similar to the disulfideimidate cyclization describedabove. Halogenated 3-hydroxyisothiazoles can be prepared by a methodsimilar to the halogenation of 3-alkoxyisothiazoles described above. Themethods of W. D. Crow and N. J. Leonard, J. Org. Chem., 30, 2660-2665(1965), Goerdeler and Miller, Chem. Ber. 96, 944-954 (1963), and W. R.Hatchard, J. Org. Chem., 28, 2163-2164 (1963), and an extension of themethod of Goerdeler and Keuser, Chem. Ber., 97, 3106 (1964), whichinvolves the cyclization of a substituted α-cyanothiomalonamide with ahalogenating agent, are also useful.

Among the 3-hydroxyisothiazoles which can be reacted with alkyl halidesto produce the 3-alkoxyisothiazoles of the invention are:

3-hydroxyisothiazole,

4-bromo-3-hydroxyisothiazole,

4-chloro-3-hydroxyisothiazole,

5-benzyl-3-hydroxyisothiazole,

5-bromo-3-hydroxyisothiazole,

5-chloro-3-hydroxyisothiazole,

4,5-dichloro-3-hydroxyisothiazole,

4,5-dibromo-3-hydroxyisothiazole,

4-chloro-5-bromo-3-hydroxyisothiazole,

4-bromo-5-chloro-3-hydroxyisothiazole,

4-chloro-5-benzyl-3-hydroxyisothiazole,

4-bromo-5-benzyl-3-hydroxyisothiazole,

4-methyl-3-hydroxyisothiazole,

4-ethyl-3-hydroxyisothiazole,

4-butyl-3-hydroxyisothiazole,

4-methyl-5-ethyl-3-hydroxyisothiazole,

4,5-dimethyl-3-hydroxyisothiazole,

4-methyl-5-chloro-3-hydroxyisothiazole,

4-propyl-5-chloro-3-hydroxyisothiazole,

4-butyl-5-chloro-3-hydroxyisothiazole,

4-methyl-5-bromo-3-hydroxyisothiazole,

4-ethyl-5-bromo-3-hydroxyisothiazole,

4-ethyl-5-benzyl-3-hydroxyisothiazole,

4-propyl-5-benzyl-3-hydroxyisothiazole,

4-cyano-5-methylsulfinyl-3-hydroxyisothiazole,

4-cyano-5-ethylsulfinyl-3-hydroxyisothiazole,

4-cyano-5-benzylsulfinyl-3-hydroxyisothiazole,

4-cyano-5-methylsulfonyl-3-hydroxyisothiazole,

4-cyano-5-butylsulfonyl-3-hydroxyisothiazole,

4-cyano-5-benzylsulfonyl-3-hydroxyisothiazole,

4-carboxy-3-hydroxyisothiazole,

4-carbamoyl-3-hydroxyisothiazole,

4-nitro-3-hydroxyisothiazole,

4-carboxy-5-methylthio-3-hydroxyisothiazole,

4-carbamoyl-5-methylthio-3-hydroxyisothiazole,

4-cyano-5-n-butylamino-3-hydroxyisothiazole,

4-cyano-5-ethylamino-3-hydroxyisothiazole

4-iodo-3-hydroxyisothiazole,

4-cyano-3-hydroxyisothiazole,

4-carbethoxy-3-hydroxyisothiazole,

4-nitro-5-chloro-3-hydroxyisothiazole,

4-cyano-5-methyl-3-hydroxyisothiazole

5-methyl-3-hydroxyisothiazole,

4-bromo-5-methyl-3-hydroxyisothiazole,

4-cyano-5-methylthio-3-hydroxyisothiazole,

5-phenyl-3-hydroxyisothiazole,

4-carbamoyl-5-anilino-3-hydroxyisothiazole, and

4-cyano-5-anilino-3-hydroxyisothiazole.

By way of demonstration, the following examples are offered toillustrate this invention and are not to be construed as limitationsthereof. Examples 1 to 30 are tabulated in Table I, which lists theirformulas, elemental analyses, and melting points. Specific preparationsof Examples 1, 6, 8, 13, 15, 16, 17, 18, 19, and 20 are set out below toillustrate the various methods of preparing the 3-alkoxyisothiazoles ofthe invention.

EXAMPLE 1 Preparation of 3-methoxyisothiazole

To a solution of 43 g. (0.25 mole) of β,β'-dithiodipropionitrile and 80g. (2.5 mole) of methanol in 250 ml. of ethylene dichloride was added at0°-5° C. 55 g. (1.5 mole) of anhydrous hydrogen chloride over 1 hour.The solution was then allowed to stand for several days at 5°-10° C.,during which time dimethyl β,β'-dithiodipropionimidate dihydrochlorideprecipitated as a white solid. Filtration and drying gave 68 g. (88% ofproduct.

To a suspension of 61.8 g. (0.2 mole) of dimethylβ,β'-dithiodipropionimidate dihydrochloride in 650 ml. of ethyl acetateat 25° C. was added over 1 hour 44.7 g. (0.63 mole) of chlorine. Afterchlorination, the reaction mixture was stirred for 1 hour, then filteredto give 44.4 g. of 3-methoxyisothiazole hydrochloride as a white solid.This material was dissolved in 100 ml. of water, neutralized with solidsodium bicarbonate and extracted thoroughly with ether. The etherextracts were dried over anhydrous magnesium sulfate and evaporated togive an oil residue which on distillation yielded 26.8 g. (58%) of3-methoxyisothiazole, b.p. 147°-50° (760 mm).

EXAMPLE 6 Preparation of 3-dodecoxyisothiazole

To a slurry of 10.7 g. (0.25 mole) of sodium hydride (56% mineral oildispersion) in 60 ml. of dimethylsulfoxide was added slowly at 25° C. asolution of 3-hydroxyisothiazole in 60 ml. of dimethylsulfoxide.Hydrogen gas was evolved vigorously and after addition 5.3 liters hadbeen collected. To the resulting slurry was then added over 15 minutes49.8 g. (0.2 mole) of 1-bromododecane. After stirring for 18 hours at25° C., the reaction was heated to 80° C. for 1.5 hours. The reactionmixture was then diluted with 300 ml. of water and was extractedthoroughly with ether. The combined ether extracts were washed withwater, dried over anhydrous magnesium sulfate, and evaporated to give anoil residue. This latter product on vacuum distillation gave 11.1 g.(21%) of 3-dodecoxyisothiazole, b.p. 142 (0.6 mm).

EXAMPLE 8

Preparation of 3-benzyloxyisothiazole

To a solution of 20.2 g. (0.2 mole) of 3-hydroxyisothiazole in 100 ml.of methanol was added 47.5 g. (0.22 mole) of 25% methanolic sodiummethoxide solution, maintaining the temperature at 25°-30° C. To theresulting solution was then added dropwise at 25° C. 25.2 g. (9.2 mole)of benzyl chloride in 50 ml. of methanol. The reaction solution was thenheated at reflux for 5 hours, during which time sodium chlorideprecipitated as a white solid. The resulting slurry was evaporated to anoil-solid mixture, which was slurried in ether and filtered. The ethersolution was evaporated, and the oil residue was vacuum distilled toyield 18.7 g. (49%) of 3-benzyloxyisothiazole, b.p. 110° C. (0.3 mm).

EXAMPLE 13 Preparation of 3-allyloxyisothiazole

To a slurry of 10.7 g. (0.22 mole) of sodium hydride (56% mineral oildispersion) in 60 ml. of dimethylformamide was added slowly at 25° C.20.2 g. (0.2 mole) of 3-hydroxyisothiazole in 60 ml. ofdimethylformamide. Hydrogen gas was evolved vigorously and at thecompletion of addition 5.2 liters had been collected. To the resultingsolution was then added dropwise at 25° C. 24.2 g. (0.2 mole) of allylbromide. After stirring at 25° C. for several hours, the reactionsolution was diluted with water and extracted thoroughly with ether. Theether extracts were washed with water, dried over anhydrous magnesiumsulfate, and evaporated to an oil residue. This latter material wasvacuum distilled to give 7.3 g. (26%) of 3-allyloxyisothiazole, b.p. 60°(18 mm).

EXAMPLE 15 Preparation of 4-bromo-3-methoxyisothiazole

To a solution of 9.2 g. (0.08 mole) of 3-methoxyisothiazole in 20 ml. ofglacial acetic acid was added dropwise at 25° C. a solution of 12.8 g.(0.08 mole) of bromine in 20 ml. of glacial acetic acid. After stirringovernight the slurry which had formed was poured into 400 g. ofice-water and allowed to stand. The precipitated solid was extractedinto ether, and the aqueous phase was neutralized with solid sodiumbicarbonate and extracted with ether again. The combined ether extractwas dried over anhydrous magnesium sulfate and evaporated to leave anoil residue. This material was distilled to give 11.1 g. (72%) of4-bromo-3-methoxyisothiazole, b.p. 70° C. (5 mm), which solidified oncooling in ice.

EXAMPLE 16 Preparation of 4-iodo-3-methoxyisothiazole

To a solution of 1.15 g. (0.01 mole) of 3-methoxyisothiazole in 5 ml. ofglacial acetic acid was added dropwise over 10 minutes 1.80 g. (0.011mole) of iodine monochloride. After standing for several days thereaction solution was poured onto ice to precipitate an oil, which oncontinued washing with water gave after filtering and drying 1.0 g.(42%) of 4-iodo-3-methoxyisothiazole as a tan solid. Crystallizationfrom hexane gave this product as a white solid, m.p. 61°-63° C.

EXAMPLE 17 Preparation of 4-nitro-3-methoxyisothiazole

To a solution of 10 ml. of concentrated sulfuric acid and 2 g. (0.022mole) of 70% nitric acid was added over several minutes 2.3 g. (0.02mole) of 3-methoxyisothiazole. The temperature rose to 40° C. and wascontrolled at that point by cooling. After stirring for 5 hours thereaction solution was poured into 30 ml. of ice-water to precipitate 0.5g. (16%) of 4-nitro-3-methoxyisothiazole as a white solid, m.p.118°-122° C.

EXAMPLE 18 Preparation of 4-cyano-3-methoxyisothiazole

To a solution of 38.8 g. (0.2 mole) of 4-bromo-3-methoxyisothiazoleprepared as in Example 15 in 80 ml. of dimethylformamide was added 54 g.(0.6 mole) of cuprous cyanide. The mixture was stirred and heated atreflux for 1 hour. Then the reaction mixture was cooled to 25° C., and40 g. (0.81 mole) of sodium cyanide in 120 ml. of water was added inportions. The mixture exothermed to 60°-70° C. and was allowed again tocool to 25° C. The reaction solution was then extracted thoroughly withether. The ether extracts were washed with 10% sodium cyanide solutionand then water. After drying over anhydrous magnesium sulfate andevaporation 23.4 g. (83%) of 4-cyano-3-methoxyisothiazole was obtainedas a white solid, m.p. 60°-62° C. after crystallization from ligroin(90°-120°).

EXAMPLE 19 Preparation of 4-carbamoyl-3-methoxyisothiazole

A solution of 2.8 g. (0.02 mole) of 4-cyano-3-methoxyisothiazoleprepared as in Example 18 in 30 ml. of 75% sulfuric acid was heated at70° C. for 0.5 hour. The solution was then cooled and poured into ice togive after filtration and drying 0.95 g. of4-carbamoyl-3-methoxyisothiazole, m.p. 165°-168° C. By continuous etherextraction of the aqueous filtrate an addition 1.13 g. of4-carbamoyl-3-methoxyisothiazole was obtained to give a total yield of2.08 g. (66%).

EXAMPLE 20 Preparation of 4-carboxy-3-methoxyisothiazole

To a solution of 7.9 g. (0.05 mole) of 4-carbamoyl-3-methoxyisothiazoleprepared as in Example 19 in 90 ml. of 80% sulfuric acid at 10°-15° C.was added slowly beneath the surface of the liquid a solution of 9.5 g.(0.137 mole) of sodium nitrite in 13 ml. of H₂ O. When addition wascomplete the solution was allowed to come to 25° C., and then was heatedto 60° C. for several minutes. After cooling to 25° C. the reactionsolution was poured onto ice to precipitate 3.64 g. (46%) of4-carboxy-3-methoxyisothiazole as a white solid, m.p. 182°-185° C.

                                      TABLE I                                     __________________________________________________________________________    3-Alkoxyisothiazole Examples                                                                           ZOY                                                                           ||                                                          ∥------∥                                                    ∥∥                                                          ∥N                                                                   |∠                                                             Z'S                                                  Analysis**                                                                    Ex.                                                                           No. Z   Z'                                                                              b.p. / m.p.   Y      C     H     N     S       Halogen              __________________________________________________________________________        H   H  72°                                                                         (52 mm)                                                                             CH.sub.3                                                                              41.77(41.7)                                                                         4.35(4.4)                                                                           11.95(12.2)                                                                         27.90(27.8)                   2   H   H  36°                                                                         (0.3 mm)                                                                            C.sub.3 H.sub.7 --n                                                                   50.42(50.4)                                                                         6.49(6.3)                                                                           9.92(9.8)                                                                           22.44(22.4)                   3   H   H 95    (26 mm)                                                                             CH(CH.sub.3).sub.2                                                                    50.56(50.4)                                                                         6.35(6.3)                                                                           9.80(9.8)                                                                           22.05(22.4)                   4   H   H 42    (0.1 mm)                                                                            C.sub.4 H.sub.9 --n                                                                   54.06(53.5)                                                                         7.21(7.0)                                                                           8.76(8.9)                                                                           20.24(20.4)                   5   H   H 61    (0.4 mm)                                                                            C.sub.6 H.sub.13 --n                                                                  58.59(58.4)                                                                         7.98(8.1)                                                                           7.51(7.6)                                                                           17.18(17.3)                   6   H   H 142   (0.6 mm)                                                                            C.sub.12 H.sub.25 --n                                                                 68.39(66.9)                                                                         9.90(10.0)                                                                          4.82(4.7)                                                                           11.72(11.9)                   7   H   H 94    (0.5 mm)                                                                            CH.sub.2 OCH.sub.3                                                                    41.14(41.1)                                                                         5.42(5.5)                                                                           9.70(9.6)                                                                           22.07(21.9)                   8   H   H 110   (0.3 mm)                                                                            CH.sub.2 C.sub.6 H.sub.5                                                              62.27(62.9)                                                                         4.73(4.7)                                                                           7.64(6.3)                                                                           16.63(16.8)                   9   H   H 66-9°*                                                                             CH.sub.2 C.sub.6 H.sub.2 Cl.sub.3                                                     42.53(40.9)                                                                         2.52(2.0)                                                                           4.22(4.7)                                                                           9.86(10.8)                                                                           Cl, 36.13 (36.1)       10  H   H  94°                                                                         (1.25 mm)                                                                           CH.sub.2 CO.sub.2 C.sub.2 H.sub.5                                                     45.54(44.9)                                                                         5.05(4.8)                                                                           6.94(7.5)                                                                           16.70(17.1)                   11  H   H 80    (0.1 mm)                                                                            --C.sub.2 H.sub.4 N(C.sub.2 H.sub.5).sub.2                                            53.38(54.0)                                                                         7.70(8.0)                                                                           14.05(14.0)                                                                         16.26(16.0)                   12  H   H 56    (0.35 mm)                                                                           --C.sub.2 H.sub.5 Cl                                                                  38.07(36.9)                                                                         4.32(3.7)                                                                           7.79(8.6)                                                                           19.26(19.63)                                                                         Cl, 21.67 (21.3)       13  H   H 60    (18 mm)                                                                             --CH.sub.2 CH=CH.sub.2                                                                51.43(51.2)                                                                         4.95(4.9)                                                                           9.58(9.9)                                                                           22.59(22.8)                   14  H   H 65    (0.4 mm)                                                                            --CH.sub.2 C.tbd.CH                                                                   51.37(51.7)                                                                         3.98(3.6)                                                                           9.75(10.1)                                                                          23.01(23.0)                   15  Br  H  70°                                                                         (5 mm)                                                                              CH.sub.3                                                                              24.82(24.7)                                                                         2.18(2.1)                                                                           7.20(7.2)                                                                           16.21(16.5)                                                                          Br, 40.48 (41.2)       16  I   H 61-30*      CH.sub.3                                                                              19.43(19.9)                                                                         1.50(1.7)                                                                           5.51(5.8)                                                                           13.32(13.3)                                                                          I, 52.15 (52.7)        17  NO.sub.2                                                                          H 118-22°*                                                                           CH.sub.3                                                                              30.13(30.0)                                                                         2.60(2.5)                                                                           17.49(17.5)                                                                         19.95(20.0)                   18  CN  H 60-2°*                                                                             CH.sub.3                                                                              42.40(42.8)                                                                         2.98(2.9)                                                                           19.98(20.0)                                                                         22.44(22.8)                   19  CONH.sub.2                                                                        H 165-68°*                                                                           CH.sub.3                                                                              38.16(38.0)                                                                         3.78(3.8)                                                                           17.60(17.7)                                                                         20.24(20.3)                   20  CO.sub.2 H                                                                        H 182-5°*                                                                            CH.sub.3                                                                              38.13(37.7)                                                                         3.13(3.1)                                                                           8.74(8.8)                                                                           20.02(20.1)                   21  Br  H 115   (0.3 mm)                                                                            C.sub.6 H.sub.13 --n                                                                  41.26(40.9)                                                                         5.47(5.3)                                                                           4.21(5.3)                                                                           12.01(12.12)                                                                         Br, 30.65(30.3)        22  CN  H 40-2°*                                                                             C.sub.6 H.sub.13 --n                                                                  56.83(57.1)                                                                         6.51(6.7)                                                                           13.18(13.3)                                                                         15.13(15.2)                   23  CO.sub.2 H                                                                        H 78-9°*                                                                             C.sub.6 H.sub.13 --n                                                                  51.91(52.4)                                                                         6.34(6.6)                                                                           6.07(6.1)                                                                           12.47(13.9)                   24  CN  H 73-5°*                                                                             C.sub.12 H.sub.25 --n                                                                 65.04(65.3)                                                                         8.72(8.8)                                                                           9.38(9.5)                                                                           10.72(10.9)                   25  CO.sub.2 H                                                                        H  87-90°*                                                                           C.sub.12 H.sub.25 --n                                                                 61.32(61.3)                                                                         8.78(8.6)                                                                           5.03(4.5)                                                                           9.91(10.2)                    26  H   Cl                                                                               46°                                                                         (0.05 mm)                                                                           CH.sub.2 OCH.sub.3                                                                    33.01(33.4)                                                                         3.43(3.3)                                                                           7.86(7.8)                                                                           18.61(17.8)                                                                          Cl, 20-46(19.2)        27  Br  H  50°                                                                         (0.05 mm)                                                                           C.sub.3 H.sub.7 --n                                                                   33.13(32.4)                                                                         3.79(3.6)                                                                           6.08(6.3)                                                                           14.14(14.4)                                                                          Br, 35.40 (36.0)       28  CN  H  71°                                                                         (0.025 mm)                                                                          C.sub.3 H.sub.7 --n                                                                   50.02(50.0)                                                                         5.19(4.8)                                                                           16.34(16.7)                                                                         19.28(19.1)                   29  CONH.sub.2                                                                        H  97-98°*                                                                     C.sub.3 H.sub.7 --n                                                                 43.50(45.2)                                                                           5.62(5.4)                                                                           14.30(15.0)                                                                         17.37(17.2)                         30  NH.sub.2                                                                          H 149-50*     C.sub.3 H.sub.7 --n.HCl                                                               37.28(37.0)                                                                         5.71(5.7)                                                                           14.19(14.4)                                                                         16.71(16.4)                                                                          17.88                  __________________________________________________________________________                                                           (18.2)                   *Melting Point                                                               **The number parenthesized represents the theoretical value, as               calculated, using the empirical formula of each compound.                

The novel alkoxyisothiazoles and salts of this invention are biocidallyactive compounds, and as such, are suitable for the control of variousliving organisms, including microorganisms. They are useful asbactericidal, algaecidal, fungicidal, and nematocidal agents, forexample.

Antibacterial and antifungal activity were evaluated by the SerialDilution Test (Broth Titor Test) wherein a series of broths containingvarying dilutions of a test compound and an organism are halved startingwith 1:1,000. The values obtained which are also shown in Table IIrepresent the maximum dilution in parts per millions at which thecompound under evaluation renders complete control of the organism.Staphylococcus aureus (S. aureus) and Escherichia coli, (E. coli) werethe bacterial organisms employed in this test, and the fungi employedwere Aspergillus niger (A. niger) and Rhizopus stolonifer (R. stol.).

                  TABLE II                                                        ______________________________________                                        MICROBIOLOGICAL ACTIVITY                                                      (minimum microbistatic concentration, ppm)                                    Example Bacteria         Fungi                                                No.     S. aureus  E. coli.  A. niger                                                                              R. Stol.                                 ______________________________________                                        1       >1000      1000      >500    >500                                     2       1000       1000      500     500                                      4       1000       500                                                        5       250        >1000     63      16                                       6       500        1000      >500    >500                                     7       125        125                                                        8       250        250       >500    500                                      9       500        >1000     250     125                                      10      1000       1000      >500    >500                                     11      1000       500       >500    >500                                     12      1000       1000      >500    >500                                     13      1000       1000      >500    >500                                     14      1000       500       >500    500                                      15      1000       1000      >500    >500                                     16      1000       1000      250     250                                      18      1000       1000      >500    >500                                     19      500        1000      >500    >500                                     20      >1000      >1000                                                      21      250        >1000     500     31                                       22      63         1000      250     31                                       24      1000       1000                                                       25      31         >1000     500     250                                      26      250        250       250     125                                      ______________________________________                                    

3-Alkoxyisothiazoles were also evaluated as algaecides by the FitzgeraldTest (Applied Microbiology, 7, 205-211, No. 4, 1959).

The alkoxyisothiazoles can also be used in seed treatment applications.By seed treatment is meant the disseminating of a biocidally activematerial over a seed subject to the attack of microorganisms, andparticularly fungi, in an amount which is effective to control suchmicroorganisms without deleteriously effecting such seed. In mostcircumstances, the biocidally active material, in this case, thealkoxyisothiazoles or compositions containing them, will be applied tothe surface area of the seeds to be treated. This may be accomplished bymeans common to the art, such as slurrying, socking, dusting, sprayingand the like.

Evaluation of the alkoxyisothiazoles with regard to further pesticidalactivity demonstrated their use as nematocides.

For the nematode test, soil was homogeneously inoculated with amacerated blend of tomato roots heavily knotted with the root-knotnematode. Ten ml. of a test solution of the 3-alkoxyisothiazole beingevaluated was added to 200 ml. of the inoculated soil in a 16 oz. jar togive a concentration by volume of about 60, 30, or 15 ppm. The jar wasthen shaken to insure thorough mixing and kept capped for 72 hours. Thesoil was then placed into a 3-inch deep plastic plant pot and allowed toair for about 24 hours after which time 3 cucumber (Cucumis sativus)seeds were planted. About 23 days thereafter, the cucumber plants wereremoved from the soil and the root systems examined for the presence ofknots. A total of 50 knots is considered as no control (-) and less thanthat as a measure of control.

                  TABLE III                                                       ______________________________________                                        NEMATOCIDAL ACTIVITY                                                          Example   Number of Knots                                                     No.       60 ppm      30 ppm      15 ppm                                      ______________________________________                                        2         20          --                                                      4         0           --                                                      5         0           47                                                      8         0           21                                                      12        8           0           20                                          14        4                                                                   26        8                                                                   Control   50-100                                                              ______________________________________                                    

Generally, control of a living organism is achieved in accordance withthis invention by contacting the organism with an alkoxyisothiazole inan amount which is effective to control the organism. Any of thetechniques known in the art can be employed to disseminate thealkoxyisothiazoles in a manner so as to achieve the desired contact withthe organism to be controlled. Spraying and fumigating are typical ofsuch techniques.

The compounds of this invention can be utilized as slimicides,algaecides, bactericides, fungicides or combinations thereof in anylocus and particularly in aqueous media, such as water-cooling systems,swimming pools, paper pulp processes, water-based paints, and the like.In addition, these compounds and/or compositions containing them canfunction as preservatives, and especially fabric preservatives, soapadditives, sanitizing agents, preservatives for metal working compounds,and the like.

In general, a locus subject to attack by microorganisms can be protectedin accordance with this invention by incorporating into said locus analkoxyisothiazole in an amount which is effective to control saidmicroorganisms. The exact amount of alkoxyisothiazole required will, ofcourse, vary with the medium being protected, the microorganisms beingcontrolled, the particular alkoxyisothiazoles or compositions containingthe alkoxyisothiazoles being employed and the like. Typically, in aliquid medium, excellent control is obtained when the alkoxyisothiazolesare incorporated in the range of 0.1 to 10,000 parts per million (ppm.)or 0.00001 to 1% based on the weight of the medium. A range of 1 to 2000ppm. is preferred.

The term "control", as employed in the specification and claims of thisapplication, is to be construed as the effect of any means whichadversely affects the existence or growth of any living organism ormicroorganism. Such effect may comprise a complete killing action,eradication, arresting in growth, inhibition, reduction in number or anycombination thereof.

The alkoxyisothiazoles can also be used as agricultural fungicides. Assuch, they are particularly valuable when formulated in a fungicidalcomposition. Such compositions normally comprise an agronomicallyacceptable carrier and the compounds disclosed herein as the activeagent or agents. Where necessary to desirable, surfactants or otheradditives may be incorporated to give uniformly formulated mixtures. By"agronomically acceptable carrier" is meant any substance which can beutilized to dissolve, dispense or diffuse the chemical incorporatedtherein without impairing the effectiveness of the toxic agent and whichdoes no permanent damage to such environment as soil, equipment andagronomic crops.

For use as pesticides, the compounds of this invention are usually takenup in an agronomically acceptable carrier or formulated so as to renderthem suitable for subsequent dissemination. For example, thealkoxyisothiazoles may be formulated as wettable powders, emulsionconcentrates, dusts, granular formulations, aerosols or flowableemulsifiable concentrates. In such formulations, the alkoxyisothiazolesare extended with a liquid or solid carrier and, when desired, suitablesurfactants are likewise incorporated.

Thus, compounds of this invention can be dissolved in a water-miscibleliquid such as ethanol, isopropanol, acetone, and the like. Suchsolutions are easily extended with water.

The isothiazoles can be taken up on or mixed with a finely particledsolid carrier, as for example, clays, inorganic silicates, carbonates,and silicas. Organic carriers may also be employed. Dust concentratesare commonly made wherein alkoxyisothiazoles are present in the range of20 to 80%. For ultimate applications these concentrates are normallyextended with additional solid from about 1 to 20%.

Wettable powder formulations are made by incorporating the compounds ofthis invention in an inert, finely divided solid carrier along with asurfactant which may be one or more emulsifying, wetting, dispersing orspreading agents or blend of these. The alkoxyisothiazoles are usuallypresent in the range of 10 to 80% by weight and the surfactants in from0.5 to 10% by weight. Commonly used emulsifying and wetting agentsinclude polyoxyethylated derivatives of alkylphenols, fatty alcohols,fatty acids and alkylamines; alkylarene sulfonates and dialkylsulfosuccinates. Spreading agents include such materials as glycerolmannitan laurate and a condensate of polyglycerol and oleic acidmodified with phthalic anhydride. Dispersing agents include suchmaterials as the sodium salt of the copolymer of maleic anhydride and anolefin such as diisobutylene, sodium lignin sulfonate and sodiumformaldehydenaphthalene sulfonates.

One convenient method for preparing a solid formulation is to impregnatethe isothiazole toxicant onto the solid carrier by means of a volatilesolvent, such as acetone. In this manner, adjuvants, such as activators,adhesives, plant nutrients, synergists and various surfactants, may alsobe incorporated.

Emulsifiable concentrate formulations may be prepared by dissolving theisothiazoles of this invention in an agronomically acceptable organicsolvent and adding a solventsoluble emulsifying agent. Suitable solventsare usually water-immiscible and may be found in the hydrocarbon,chlorinated hydrocarbon, ketone, ester, alcohol and amide classes oforganic solvents. Mixtures of solvents are commonly employed. Thesurfactants useful as emulsifying agents may constitute about 0.5 to 10%by weight of the emulsifiable concentrate and may be anionic, cationicor nonionic in character. Anionic surfactants include alcohol sulfatesor sulfonates, alkylarene sulfonates and sulfosuccinates. Cationicsurfactants include fatty acid alkyl amine salts and fatty acid alkylquaternaries. Non-ionic emulsifying agents include ethylene oxideadducts of alkylphenols, fatty alcohols, mercaptans and fatty acids. Theconcentration of the active ingredients may vary from 10 to 80%,preferably in the range of 25 to 50%.

For use as phytopathogenic agents, these compounds should be applied inan effective amount sufficient to exert the desired biocidal activity bytechniques well known in the art. Usually, this will involve theapplication of the alkoxyisothiazoles to the locus to be protected in aneffective amount when incorporated in an agronomically acceptablecarrier. However, in certain situations it may be desirable andadvantageous to apply the compounds directly onto the locus to beprotected without the benefit of any substantial amount of carrier. Thisis a particularly effective method when the physical nature of thealkoxyisothiazoles is such as to permit what is known as "low-volume"application, that is, when the compounds are in liquid form or highlysoluble in higher boiling solvents, so that they can be dissolvedtherein at high concentrations.

The application rate will, of course, vary depending upon the purposefor such application, the alkoxyisothiazoles being utilized, thefrequency of dissemination and the like.

For use as bactericides and fungicides, dilute sprays may be applied atconcentrations of 0.05 to 20 pounds of the active alkoxyisothiazoleingredient per 100 gallons of spray. They are usually applied at 0.1 to10 pounds per 100 gallons and preferably at 0.125 to 5 pounds per 100gallons. In more concentrated sprays, the active ingredient is increasedby a factor of 2 to 12. With dilute sprays, applications are usuallymade to the plants until run-off is achieved, whereas with moreconcentrated or low-volume sprays the materials are applied as mists.

The compounds of this invention can be utilized as the sole biocidalagents or they can be employed in conjunction with other fungicides,insecticides, nematocides, and other comparable pesticides.

It is to be understood that changes and variations may be made withoutdeparting from the spirit and scope of the invention as defined by theappended claims.

We claim:
 1. A compound of the formula ##EQU8## wherein Y is an alkylgroup of 1 to 18 carbon atoms; a cycloalkyl group of 3 to 8 carbonatoms; a benzyl group; a halogen-, (C₁ -C₄)alkyl-, or (C₁-C₄)alkoxy-substituted benzyl group; a carbalkoxyalkyl group of up to 12carbon atoms; a dialkylaminoalkyl group of up to 12 carbon atoms; ahaloalkyl group of up to 12 carbon atoms; an alkoxyalkyl group of up to12 carbon atoms; an alkylthioalkyl group of up to 12 carbon atoms; analkenyl group of up to 12 carbon atoms; or an alkynyl group of up to 12carbon atoms;Z is hydrogen, halogen, or a (C₁ -C₄)alkyl group; and Z' ishydrogen, halogen, or a (C₁ -C₄)alkyl group; and the salts thereof witha strong acid.
 2. A compound according to claim 1 wherein Y is a benzylgroup.
 3. A compound according to claim 1 wherein Y is an alkyl group of1 to 18 carbon atoms.
 4. A compound according to claim 3 wherein Z andZ' are hydrogen.
 5. A compound according to claim 4 wherein Y is an-hexyl group.